The overall goal of this National Cooperative Drug Discovery Group (NCDDG) project is to develop telomere and telomerase-interactive agents that improve the survival and quality of life of patients with cancer. Telomeres are repetitive sequences (TTAGGG in humans) at the ends of chromosomes, which have been called "chemical bookends." The integrity of telomeres is vital for cell survival. Unfortunately, as cells divide (age), the length of telomeres gradually decreases which leads to chromosome instability. When telomeres become very short, cells undergo a crisis. The cells that survive are immortal and have an increase in the enzyme telomerase. Telomerase is a reverse transcriptase that synthesizes and maintains telomeres. Important to this application are two observations: l) tumor cells have shorter telomeres than do normal cells (because the tumor cells have undergone more divisions); and 2) telomerase is produced in tumor cells (and not in normal cells). These two observations give us unique targets which are different in tumor cells versus normal cells and an opportunity to develop agents that affect tumor cells but not normal cells. The Specific Aims of Program 4 include: l) to determine if telomeres are indeed shorter in primary and metastatic human tumors (versus normal cells); 2) to determine if the enzyme telomerase is present in primary and metastatic human tumors (versus normal cells); 3) to establish preclinical in vivo models relevant to potential clinical trials with telomere and telomerase-interactive agents and to test candidate agents in those models. This program works with human breast, lung, head and neck, colon and ovarian cancer specimens. Our team has already gathered preliminary information that tumor cells taken directly from patients have telomeres in tumors that are shorter than telomeres taken from normal cells from the same patient. In addition, we have documented that the enzyme telomerase is present in tumor cells taken directly from patients. These findings solidify the selection of telomeres/telomerase as drug development targets. This program will provide us with increased knowledge about our two targets: telomeres and telomerase in tumors taken directly from patients. That work should give us leads to improve the specificity of our telomere/telomerase-interactive agents (i.e., to maximize effectiveness/minimize toxicities). The program also includes the development of in vivo models as well as testing of our candidate compounds in those models. These models are designed to reflect true clinical situations that should lead to rapid clinical trials of compounds developed by this NCDDG.